WO1995016677A1 - Nouveau derive de pyrimidine et composition medicinale - Google Patents

Nouveau derive de pyrimidine et composition medicinale Download PDF

Info

Publication number
WO1995016677A1
WO1995016677A1 PCT/JP1994/002114 JP9402114W WO9516677A1 WO 1995016677 A1 WO1995016677 A1 WO 1995016677A1 JP 9402114 W JP9402114 W JP 9402114W WO 9516677 A1 WO9516677 A1 WO 9516677A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
general formula
compound
methyl
yield
Prior art date
Application number
PCT/JP1994/002114
Other languages
English (en)
Japanese (ja)
Inventor
Akihiro Ohkubo
Torataro Minegishi
Tadashi Mizuta
Hiroaki Sato
Masashi Yamada
Tomoko Yabuta
Original Assignee
Nkk Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nkk Corporation filed Critical Nkk Corporation
Priority to EP95902967A priority Critical patent/EP0685467A4/fr
Publication of WO1995016677A1 publication Critical patent/WO1995016677A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a novel pyrimidine derivative and a pharmaceutical composition containing the pyrimidine derivative as an active ingredient, particularly to an angiotensin II antagonist. Since the pyrimidine derivative according to the present invention has an angiotensin II antagonistic action, it is useful for various circulatory diseases, such as hypertension, heart disease, stroke or arteriosclerosis. Background art
  • the renin-angiotensin system is known as a major pressor factor in living organisms.
  • active renin proteolytic enzyme
  • angiotensinogen angiotensinogen
  • AI angiotensin I
  • ACE angiotensin-converting enzyme
  • the antagonist of ⁇ can be used for treating cardiovascular diseases such as hypertension caused by ⁇ .
  • angiotensin ⁇ analogs such as [Sar 1 , Ala 8 ] All (salalasin) have been reported to have ⁇ antagonist activity. It had the disadvantage of being short and ineffective at oral administration.
  • imidazole derivatives are described in many patent publications as non-peptide antagonists. For example, JP-A-56-71074, JP-A-57-98270, JP-A-58-157768, JP-A-63-23868, and JP-A-1-287071.
  • pyrimidine derivatives are also disclosed in EP-0407342, JP-A-3-133964, JP-A-3-197466, JP-A-4-120072, JP-A-4-230370, JP-A-4-1261156. And JP-A-4-330073 and EP-0445811. Disclosure of the invention
  • the present inventor has conducted intensive studies to obtain an orally administrable and highly safe cardiovascular agent having an excellent ⁇ -antagonistic action.
  • --A group of pyrimidine derivatives having different structures and having a substituted phenylalkyl group at the 5-position of the pyrimidine ring has been found to have strong ⁇ antagonistic activity.
  • the present invention is based on such findings.
  • the present invention provides a compound of the general formula (I):
  • R 1 and R 2 may be the same or different and each represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a lower alkylthio group, an acetyl group, a halogen atom, a phenyl group.
  • R 3 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or an acetyl group;
  • X represents 0, NH or S (0) p; p represents an integer of 0 2 and m represents an integer of 12)
  • B represents a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a tetrazolyl group or a protected tetrazolyl group, and n represents an integer of 1 to 2] or a pyrimidine derivative represented by About its salt.
  • the present invention also provides a pharmaceutical composition, particularly an angiotensin antagonist, which comprises, as an active ingredient, a pyrimidine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • a pharmaceutical composition particularly an angiotensin antagonist, which comprises, as an active ingredient, a pyrimidine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.
  • a lower alkyl group means a linear or branched alkyl group having 1 to 6 (particularly 1 to 4) carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, t-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethyl Propyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl Group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-
  • the lower alkenyl group means a linear or branched alkenyl group having 2 to 6 (particularly 2 to 4) carbon atoms, such as a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group.
  • Examples of the lower alkynyl group include straight-chain or branched alkynyl having 2 to 6 (particularly 2 to 4) carbon atoms, such as alkenyl group, 3-hexenyl group, 4-hexenyl group, and 5-hexenyl group.
  • Groups such as ethynyl, ⁇ -propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2- Pentynyl group, 3-pentynyl group, 4-pentynyl group, 1-methyl-2-butynyl group, 1-methyl-13-butynyl group, 2-methyl-13-butynyl group, 3-methyl-11-butynyl group, 1, Examples include 1-dimethyl-2-propynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, and 5-hexynyl group.
  • Examples of the lower alkoxy group include a linear or branched alkoxy group having 1 to 6 (particularly 1 to 4) carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, Examples include an isobutoxy group, a t-butoxy group, an n-pentyloxy group, and an n-hexanoxy group.
  • Examples of the lower alkylthio group include a linear or branched alkylthio group having 1 to 6 (particularly 1 to 4) carbon atoms, such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, and isobutylthio.
  • Examples of the halogen atom include fluorine, chlorine, bromine, and iodine.
  • Examples of the substituent of the substituted phenyl group include a lower alkyl group having 1 to 6 (particularly 1 to 4) carbon atoms, a lower alkoxy group having 1 to 6 (particularly 1 to 4) carbon atoms, a halogen atom, Examples thereof include a nitro group, a trifluoromethyl group, a carboxyl group, and a lower alkoxycarbonyl group.
  • an alkoxycarbonyl group having 2 to 6 (particularly 2 to 4) carbon atoms for example, a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n- butoxycarbonyl group, isobutoxycarbonyl group, sec _ butoxycarbonyl group, t-butoxycarbonyl group, include power?, such as n- pentyl Ruo carboxymethyl carbonylation Le group.
  • Examples of the protected tetrazolyl group include a trityl group, a p-dimethoxybenzyl group, a 1-ethoxyshethyl group, and a t-butoxycarbonyl group.
  • R 1 represents a lower alkyl group having 1 to 6 carbon atoms
  • R 2 represents a lower alkyl group having 1 to 4 carbon atoms
  • R 3 represents hydrogen.
  • R 1 represents a methyl group, an ethyl group, a propyl group, a butyl group or a pentyl group
  • R 2 represents a methyl group, an ethyl group or a propyl group
  • R 3 represents a hydrogen atom, a methyl group or an acetyl group
  • X represents 0, m represents 1
  • B represents a cyano group, a tetrazolyl group, or a trityltetrazolyl group
  • n represents 1. Compounds are more preferred.
  • the pharmacologically acceptable salts of the compound of the present invention represented by the general formula (I) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, methylamine Organic amine salts such as salts, ethylamine salts, triethylamine salts, pyridine salts, etc .; basic amino salts such as lysine and arginine; and ammonium salts.
  • the compound of the present invention represented by the above general formula (I) may have geometric isomers, optical isomers and tautomers, and any of these isomers and any mixtures thereof may be used. Included in the present invention.
  • the compound of the present invention represented by the general formula (I) can be produced, for example, by the following method. That is, the general formula ( ⁇ ):
  • R 4 represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group
  • n represents the same meaning as described above, B ′ represents a lower alkoxycarbonyl group, a cyano group, or a protected tetrazolyl group, Y represents a halogen atom, an alkylsulfonyloxy group, or an arylsulfonyloxy group. Indicates a group
  • Bases that can be used in the reaction include alkali metals such as sodium hydroxide, potassium hydroxide, sodium hydride, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate.
  • alkali metal carbonates such as lithium and potassium hydrogen carbonate
  • organic amines such as triethylamine, diisopropylethylamine, pyridine, and N, N-dimethylaminopyridine.
  • Any solvent may be used as long as it does not participate in the reaction.
  • organic solvents such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, dioxane, tetrahydrofuran, acetone, alcohol, and the like
  • the reaction temperature is in the range of 20 to 200 t, preferably 0 to 100 ° C, and the reaction is usually completed in 1 to 48 hours.
  • Formula (la) according to the method:
  • lithium aluminum hydride / sodium borohydride and its homologs can be used.
  • a suitable Lewis acid for example, aluminum chloride, cesium chloride, etc.
  • the solvent may be any solvent as long as it does not participate in the reduction, and examples thereof include tetrahydrofuran, diethyl ether, dioxane, methanol, ethanol, and dichloromethane.
  • the reaction temperature ranges from 120 to 100 ° C, preferably from 110 to 60 ° C, and the reaction is usually completed in 30 minutes to 5 hours.
  • This alkylation reaction is usually carried out using N, N-dimethyl by using about 1-3 mol of a base and about 1-3 mol of an alkylating agent per 1 mol of the compound of the present invention represented by the above general formula (Ia).
  • the reaction can be performed in a solvent such as formamide, dimethyl sulfoxide, acetonitrile, acetone and ethyl methyl ketone.
  • a solvent such as formamide, dimethyl sulfoxide, acetonitrile, acetone and ethyl methyl ketone.
  • the base that can be used in this alkylation reaction include sodium hydride, potassium t-butoxide, potassium carbonate, and sodium carbonate.
  • alkylating agent examples include substituted halides (eg, chloride, bromide and iodide) and substituted sulfonic esters (eg, methyl p-toluenesulfonate).
  • the reaction conditions vary depending on the combination of the base and the alkylating agent used, but it is usually preferable to carry out the reaction under ice-cooling to room temperature for about 1 to 48 hours.
  • the compound of the present invention wherein R 5 of the general formulas (I b-1) and (I b-2) is a lower alkenyl group, a lower alkenyl group or an acetyl group, As in the case of the alkylation, it can be produced by reacting the compound of the present invention represented by the above general formula (Ia) with the corresponding alkenyl, alkynyl, or acetylylani.
  • the compound of the present invention wherein B of the general formula (I) is a tetrazolyl group can be produced by removing the protecting group of the corresponding compound of the present invention wherein B of the general formula (I) is a protected tetrazolyl group.
  • the conditions for deprotection are as follows: in aqueous alcohols (eg, methanol, ethanol, etc.) containing about 0.5 to 2 N hydrochloric acid or acetic acid, or in trifluoroacetic acid; It is convenient to react for about 0 hours. ⁇ —
  • the compound of the present invention in which ⁇ in the general formula (I) is a tetrazolyl group can also be produced by reacting the corresponding compound of the present invention in which ⁇ in the general formula (I) is a nitrile group with an azide derivative.
  • an azide derivative used in the reaction include sodium azide, potassium azide, trimethyltin azide, tributyltin azide, and the like.
  • a solvent that does not participate in the reaction for example, in the presence of benzene, toluene, xylene, or the like It can be produced by reacting at a temperature of 0 to 200 ° C. for 30 minutes to 1 week.
  • a compound of the general formula (IV), (Ia) or (Ib) wherein B, is a tetrazolyl group can be similarly produced from a compound having a corresponding nitrile group.
  • the compound of the present invention in which B of the general formula (I) is a carboxyl group is a compound of the present invention wherein B of the general formula (I) is a lower alkoxyl group in the presence of an acid or a base.
  • B of the general formula (I) is a lower alkoxyl group in the presence of an acid or a base.
  • the acid used in the reaction include hydrochloric acid and sulfuric acid
  • examples of the base include sodium hydroxide and potassium hydroxide.
  • the solvent a mixed solvent of water and an alcohol, for example, methanol and ethanol is preferable, and the reaction is usually completed in a temperature range from room temperature to reflux under 10 minutes to 10 hours.
  • the compound of the present invention wherein B of the general formula (I) is a lower alkoxycarbonyl group can be obtained by esterifying the corresponding compound of the present invention wherein B of the general formula (I) is a carboxyl group in the presence of an acid.
  • an acid can also be manufactured.
  • the acid used for the reaction include hydrochloric acid, sulfuric acid, and arylsulfonic acid.
  • the reaction is usually completed using the alcohol to be reacted, for example, methanol, ethanol, propanol, butanol, etc., as a solvent in a temperature range from room temperature to reflux for 1 to 24 hours.
  • R 1 and n have the same meanings as described above, and R 6 represents a nitrile group or a protected tetrazolyl group
  • R 2 , R 4 and m have the same meaning as described above, and R 7 represents a lower alkoxycarbonyl group, a hydroxymethyl group or a lower alkoxymethyl group.
  • R 1 , R 2 , R 3 and m have the same meaning as described above, and W represents a halogen atom or a nitro group
  • the starting compounds used in each of the above production methods are known per se or can be synthesized according to known methods.
  • the pyrimidine derivative represented by the general formula ( ⁇ ) can be produced according to the method described in JP-A-3-13964.
  • the biphenyl derivatives represented by the general formulas ( ⁇ ) and (Vin) can be produced according to the methods described in W0-89 / 0623, JP-A-11-118876. can do.
  • the compound of the present invention represented by the general formula (I) synthesized by the above synthesis method can be purified by a conventional purification method such as recrystallization, reprecipitation, solvent extraction, silica gel column chromatography, column chromatography using an absorbent resin, and the like. Can be purified.
  • the compound of the present invention represented by the above general formula (I) has excellent angiotensin ⁇ antagonist activity and high safety, it can be used as a pharmaceutical composition, particularly as an angiotensin ⁇ antagonist for various cardiovascular diseases. Can be used for treatment.
  • the circulatory disease include hypertension, heart disease, stroke, and arteriosclerosis, and are also useful as a therapeutic agent for ocular hypertension.
  • a pharmaceutical composition particularly an angiotensin II antagonist, comprising the compound of the present invention represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, is preferably orally administered or parenterally administered (for example, intramuscular injection, intravenous injection, subcutaneous injection, I administration, transdermal administration, etc.), and pharmaceutically acceptable adjuvants may be added to make tablets, capsules, granules, powders, pills, and fine powders. Granules, injections, rectal administration, suppositories and the like can be used.
  • Pharmaceutically acceptable adjuvants include excipients, binders, disintegrants, lubricants, buffers, preservatives, solubilizers, preservatives, flavoring agents, soothing agents, stabilizers, coloring And the like, and these can be used in an appropriate combination according to a conventional method.
  • Excipients include lactose, sucrose, glucose, sorbitol, corn starch, crystalline cellulose, etc .; binders include cellulose derivatives, gum arabic, gelatin, polyvinyl alcohol, polyvinyl ether, etc .; disintegrants: carboxymethyl cellulose Calcium and other lubricants, such as talc, magnesium stearate, — —
  • the pharmaceutical composition of the present invention comprises a compound represented by the general formula (I) as an active ingredient or a pharmacologically acceptable salt thereof, which is effective for angiotensin antagonist activity.
  • the amount for example 5-1 00 weight 0/0, preferably in an amount of 25 to 1 00% by weight.
  • the dosage varies depending on the age, body weight, sex, symptoms, administration method, administration period, therapeutic effect, etc.For oral administration, it is usually l-1000 mg, preferably 5-20 Omg per adult per day. Is usually administered in 1 to 3 divided doses.
  • 0.65 £ of sodium methoxide was suspended in 40 ml of dry 01 ⁇ 1 (N, N-dimethylformamide), stirred at room temperature for 20 minutes, and then suspended in 5- (4-Methoxycarbonylbenzyl) -1-6- 3.60 g of methyl-2-propylpyrimidin-4 (3H) -one and 40 ml of dry DMF were added, and the mixture was further stirred for 1 hour. Then, 7.35 g of 4'-bromomethyl-1- (triphenylmethyltetrazol-15-yl) biphenyl was dissolved in dry DMF 4 Oml and added dropwise to the reaction mixture, and the mixture was stirred at room temperature for 60 hours. did.
  • reaction solution was concentrated, 4 Om 1 of water was added, and the mixture was extracted twice with 150 ml of ethyl acetate.
  • the ethyl acetate extracted layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography eluting with system n-hexane: ethyl acetate (3: 1) to obtain 2.92 g of the title compound as amorphous.
  • Reference Example 51 1 5- (3-carboxybenzyl) -1,2,6-dipropyl-14- "2,1- (1H-tetrazol-15-yl) biphenyl-14-yl] methoxypyrimidine Rate: 21%, Melting point: 133 to 135 ° C
  • the ethyl acetate extract layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, added with 80 ml of methanol and 4 ml of concentrated hydrochloric acid, and stirred at room temperature for 1 hour.
  • To the reaction solution was added 4 Nm 1 of a 5 N aqueous sodium hydroxide solution, and the mixture was stirred at 80 ° C for 2 hours, concentrated under reduced pressure, added with 10 Om1 of water, and washed twice with 10 Om1 of getyl ether.
  • the resulting aqueous solution was adjusted to pH 4 with 1N hydrochloric acid, extracted twice with 10 mL of ethyl acetate, and the ethyl acetate extract layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the obtained residue was dissolved in 100 ml of dichloromethane, 11.2 g of triphenylmethyl chloride and 5.5 ml of triethylamine were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution is washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure.
  • the residue obtained is separated by chromatography on silica gel using a form: methanol (50: 1) system. To give 11.4 g of the title compound.
  • N-trityl compound was dissolved in 8 ml of dry tetrahydrofuran (THF) and stirred at 110 ° C. for 10 minutes.
  • THF dry tetrahydrofuran
  • 0.14 ml of N-methylmorpholine and 0.12 ml of ethyl ethyl chloroformate were added, and the mixture was further stirred for 10 minutes.
  • 0.14 g of sodium borohydride was quickly added at the same temperature, and the reaction solution was heated to 0 ° C.
  • 16 ml of dry methanol was gradually dropped into the reaction solution, and the mixture was stirred for 15 minutes.
  • reaction solution was concentrated, water 2 Om1 was added, and the mixture was extracted twice with 150 ml of ethyl acetate.
  • the ethyl acetate extract was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography eluting with n-hexane: ethyl acetate (2: 1) to give the title compound as amorphous as 78 g.
  • Example 1 (a) 0.39 g of the compound obtained in Example 1 (a) was dissolved in 1 Oml of dry DMF under an argon atmosphere, and the mixture was stirred at room temperature for 10 minutes. Next, 0.02 g of sodium hydride was added to the reaction solution, and the mixture was stirred for 10 minutes. After stirring, 0.10 ml of methane was added, and the mixture was stirred at room temperature for 30 hours. After completion of the reaction, 4 Om 1 of water was added to the reaction solution, and extracted twice with 3 Om 1 of ethyl acetate. The ethyl acetate extracted layer was washed with water and saturated saline, and dried over anhydrous sodium sulfate.
  • Example 8 6-Ethyl-1-5- (4-hydroxymethylbenzyl) 1-2-propyl-14-'"2,-(1H-tetrazol-1-5-yl) biphenyl-1-4-yl
  • methoxy cypyrimidine Using the compound obtained in Reference Example 26, the title compound was obtained according to the method of Example 1 above. Yield: 60%, melting point: 71-73 ° C
  • Example 17 5- (3-hydroxymethylbenzyl) -1-6-methyl-2-propyl-4-di-2,1- (1H-tetrazol-1-5-yl) biphenyl-1-4- Preparation of 1-methoxy-pyrimidine _ Yield: 3296, Melting point: 177 ⁇ 178 ° C
  • Example 20 5- (3-Methoxymethylbenzyl) -1-6-methyl-2-propyl-3-J2 '-(1H-tetrazol-15-yl) biphenyl-14-yl, methylpyrimidine Preparation of 4-one — —
  • Example 21 1 2-butyl-1-5- (3-hydroxymethylbenzyl) -1-methyl-1-41 [2 '-(1H-tetrazole-15-yl) biphenyl 4-yl 1 methoxy Preparation of cypyrimidine
  • Example 39 Using the compound obtained in Reference Example 39, the title compound was obtained according to the method of Example 1 above. Yield: 16%, melting point: 74-76 ° C
  • Example 31 1 2,6-Jetyl-5- (3-Methoxymethylbenzyl) -13- "2 '-(1H-tetrazol-1-5-yl) biphenyl-1-4-yl] methylpyrimidine — 4-on preparation
  • Example 3 7 2-butyl-1-6-ethyl-5- (3-methoxymethylbenzyl) -1-3- [2,-(1H-tetrazol-5-yl) biphenyl-1-yl, methylpyrimidine-1 4
  • Example 3 8 5- (3-Hydroxymethylbenzyl) -12-methyl-16-propyl-13- "2,1- (1 ⁇ -tetrazo-1-yl 5-yl) biphenyl-2-yl 4-methyl Preparation of pyrimidine-one
  • Example 40 2-Ethyl-5- (3-hydroxymethylbenzyl) -1-6-propyl-3-3- [2,-(1H-tetrazol-1-5-yl) biphenyl-1-4-yl, Preparation of methyl pyrimidine-1-one
  • Example 42 5- (3-Hydroxymethylbenzyl) -1,2,6-dibutyl pill-3-1 "2 '-(1H-tetrazol-1-5-yl) biphenyl-4-1-yl] methylpyrimidine-1 4-on preparation
  • Example 4 7 6-Ethyl-5- (3-hydroxymethylbenzyl) -12-methyl-4-4-_2 '-(1H-tetrazol-15-yl) biphenyl-1-4-yl] methoxy — —
  • Example 48 5- (3-Acetoxymethylpentyl) 16-methyl-12-propyl —3— “2,-(Triphenylmethyltetrazol-5-yl) biphenyl 4-yl 1 Preparation of methylpyrimidin-4-one
  • Example 36 Using the compound obtained in Reference Example 36, the title compound was obtained according to the method of Example 1 (a) above.
  • the components of the above composition were uniformly mixed to give a tablet of 20 Omg per tablet.
  • the mixture was granulated and filled into a gelatin capsule to give a capsule having a capsule content of 20 Omg per capsule.
  • the components of the above composition were dissolved in distilled water for injection so that the total amount was 1000 ml, and the solution was sealed in an ampoule to give an injection of 1 ml 1 ml.
  • Pharmacological test example 1 Angiotensin ⁇ receptor binding test
  • the affinity of the compound of the present invention for angiotensin II receptor was evaluated by displacement of a radioligand specifically bound to an angiotensin II receptor sample prepared from rat liver.
  • the liver was excised from a 5-week-old male male Wistar strain (Japanese charrriver) and homogenized in a homogenizing buffer to prepare 1096 homogenates.
  • the homogenate was centrifuged at 3000 ⁇ g for 15 minutes, and the supernatant was collected. The collected supernatant was centrifuged at 50,000 Xg for 30 minutes to obtain a pellet.
  • 20 ml of a homogenizing buffer was added, and the pellet was resuspended to prepare an angiotensin II receptor sample.
  • the thoracic aorta was isolated from a male Wistar rat weighing 150-250 g (Nippon Charisliver). After removing the attached connective tissue, endothelial cells were peeled off by rubbing the blood vessel lumen with a thread, and a ring-shaped specimen was prepared.
  • K rebs- H enseleit solution (in mM; N a C 1: 1 18, KC 1: 4. 7, C a C 1 2: 2. 55, Mg S 0 4: 1. 1 8, KH 2 P0 4: 1. 1 8, N a HC0 3 : 24. 88, gluco - S: 1 1.1) meets, kept at 3 7 ° C under 95% 02- 5% C0 2 ventilation capacity --
  • This specimen was suspended in a 5 ml organ-bath.
  • the initial tension 1. 5 g to load, after pre-incubation for 60 min, 3 X 10 _8 there Les was administered the test compound of 1 X 1 0- 8.
  • Specimen contraction was measured isometrically using an isometric transducer (UL-10GR: Minebea) and an amplifier (6 M92: NEC Sanei) and recorded with a RECTI-HORIZ-1 8K (NEC Sanei). . Table 2 shows the test results.
  • Reference compound B b) 5 32 a) 2-butyl-1-6-methyl-3- [2 '-(1H-tetrazole-5-yl) biphenyl-4-yl] methylpyrimidin-1-one: Compounds described in EP-0407342
  • the substance was administered intraperitoneally at 50 Omg and no deaths were observed in any of the administration groups.
  • the compound of the present invention represented by the general formula (I) has an excellent angiotensin II antagonistic activity and high safety, so that it can be used as an active ingredient of a pharmaceutical composition, particularly an excellent cardiovascular agent.
  • the compound of the present invention is useful as an agent for treating cardiovascular diseases such as hypertension, heart disease, stroke, and arteriosclerosis.
  • Me is a methyl group
  • Et is an ethyl group
  • Pr is a propyl group
  • Bu is a butyl group
  • Pen is a pentyl group
  • Ac is an acetyl group
  • Ph is a phenyl group.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivé de pyrimidine selon la formule générale (I) ou sel dudit dérivé présentant un antagonisme par rapport à l'angiotensine II. Dans cette formule, A représente (I-1) ou (I-2), R1 et R2 représentent chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, alcoxy, alkylthio, acétyle, halogène, phényle ou phényle substitué; R3 représente hydrogène, alkyle, alcényle, alcynyle ou acétyle; X représente O, MH ou S(O)p; p représente un nombre entier de 0 à 2; m représente 1 ou 2; B représente carboxy, alcoxycarbonyle, cyano, tétrazolyle ou tétrazolyle protégé; et n représente 1 ou 2.
PCT/JP1994/002114 1993-12-16 1994-12-16 Nouveau derive de pyrimidine et composition medicinale WO1995016677A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP95902967A EP0685467A4 (fr) 1993-12-16 1994-12-16 Nouveau derive de pyrimidine et composition medicinale.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP34361293 1993-12-16
JP5/343612 1993-12-16

Publications (1)

Publication Number Publication Date
WO1995016677A1 true WO1995016677A1 (fr) 1995-06-22

Family

ID=18362886

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1994/002114 WO1995016677A1 (fr) 1993-12-16 1994-12-16 Nouveau derive de pyrimidine et composition medicinale

Country Status (2)

Country Link
EP (1) EP0685467A4 (fr)
WO (1) WO1995016677A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7803940B2 (en) 2006-11-24 2010-09-28 Takeda Pharmaceutical Company Limited Heteromonocyclic compound or a salt thereof having strong antihypertensive action, insulin sensitizing activity and the like production thereof and use thereof for prophylaxis or treatment of cardiovascular diseases, metabolic diseases and/or central nervous system diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7423044B2 (en) 2002-09-05 2008-09-09 Wyeth Pyrimidine derivatives useful in the treatment of insulin resistance and hyperglycemia
US7897607B2 (en) 2004-04-07 2011-03-01 Takeda Pharmaceutical Company Limited Cyclic compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445811A2 (fr) * 1990-03-07 1991-09-11 Takeda Chemical Industries, Ltd. Composés hétérocycliques contenant de l'azote, leur production et leur utilisation
US5087634A (en) * 1990-10-31 1992-02-11 G. D. Searle & Co. N-substituted imidazol-2-one compounds for treatment of circulatory disorders

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0407342A3 (en) * 1989-07-06 1991-07-10 Ciba-Geigy Ag Pyrimidine derivatives
DE4493151T1 (de) * 1993-05-13 1995-07-20 Nippon Kokan Kk Pyrimidinderivate und Arzneimittel

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0445811A2 (fr) * 1990-03-07 1991-09-11 Takeda Chemical Industries, Ltd. Composés hétérocycliques contenant de l'azote, leur production et leur utilisation
US5087634A (en) * 1990-10-31 1992-02-11 G. D. Searle & Co. N-substituted imidazol-2-one compounds for treatment of circulatory disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0685467A4 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7803940B2 (en) 2006-11-24 2010-09-28 Takeda Pharmaceutical Company Limited Heteromonocyclic compound or a salt thereof having strong antihypertensive action, insulin sensitizing activity and the like production thereof and use thereof for prophylaxis or treatment of cardiovascular diseases, metabolic diseases and/or central nervous system diseases
US7998968B2 (en) 2006-11-24 2011-08-16 Takeda Pharmaceutical Company Limited Substituted pyrimidines and [1,2, 4] triazoles and the use thereof for treating prophylaxis, cardiovascular diseases, metabolic diseases and/or central nervous system diseases

Also Published As

Publication number Publication date
EP0685467A4 (fr) 1996-04-17
EP0685467A1 (fr) 1995-12-06

Similar Documents

Publication Publication Date Title
TW550259B (en) Novel compounds
CA2037630C (fr) Composes heterocycliques renfermant de l'azote, methode de production et applications correspondantes
KR100862879B1 (ko) Ｈｉｖ 인테그라제의 ｎ-치환된 하이드록시피리미디논 카복스아미드 억제제
TWI353834B (en) Aryl- and heteroarylpiperidinecarboxylate derivati
US5399566A (en) Pyridine derivatives having angiotensin II antagonism
FI114983B (fi) Menetelmä bentsimidatsoli-7-karboksylaatin C-tyyppiä olevan kiteen valmistamiseksi
KR101162047B1 (ko) ＴＡＦＩａ 억제제로서의 이미다졸 유도체
WO2009068652A1 (fr) Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
KR20060056352A (ko) 안지오텐신ⅱ 수용체 차단제 유도체들
KR20020012200A (ko) 피리미디논 화합물
HUT73783A (en) Nitrogen-containing fused-heterocycle compounds, pharmaceutical compositions containing them and process for their preparation
HUT73526A (en) Benzazepine derivative, pharmaceutical composition containing the same, and intermediate for the same
US5500427A (en) Cyclic compounds and their use
JPH05140107A (ja) ピリジン化合物
JPH05255327A (ja) 複素環式誘導体
JP2529798B2 (ja) ４−ピリミジノン誘導体、その製造方法および治療への適用
JP2023553291A (ja) Ｔｒｐｍ３媒介性障害を治療するためのアリール誘導体
JP2707390B2 (ja) シクロヘプトイミダゾ−ル誘導体及びその製造方法並びにこれを含有する薬剤
ES2216322T3 (es) Derivados de bencimidazoles y sales de estos ultimos aceptables en el plano farmaceutico.
JPH0625232A (ja) 置換インドールおよびベンズイミダゾール誘導体
WO1995016677A1 (fr) Nouveau derive de pyrimidine et composition medicinale
JP2860688B2 (ja) インドール誘導体
JPH07157485A (ja) 縮合ピリミジノン誘導体及びそれらを含有するアンジオテンシンｉｉ拮抗剤
JP2564784B2 (ja) イミダゾピリジン誘導体及びその製法
JPH07179456A (ja) アルキルベンゾフラン誘導体及びアンジオテンシンｉｉ拮抗剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

WWE Wipo information: entry into national phase

Ref document number: 1995902967

Country of ref document: EP

ENP Entry into the national phase

Ref country code: US

Ref document number: 1995 505242

Date of ref document: 19950816

Kind code of ref document: A

Format of ref document f/p: F

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWP Wipo information: published in national office

Ref document number: 1995902967

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1995902967

Country of ref document: EP